Process for the preparation of benzodiazepine compounds

ABSTRACT

compound having the formula   mixture of these compounds with a reactive derivative of a WHEREIN Q represents an acid radical of a reactive ester and R5 is as defined above. The benzodiazepine compounds are useful as a minor tranquilizer.   WHEREIN R1, R2, R3, R4, Y and A are as defined above or a mixture of these compounds with a reactive derivative of a compound having the formula   R5 is as defined above.   WHEREIN Q represents an acid radical of a reactive ester a   WHEREIN R1, R2 and R3 may be the same or different and each represents HYDROGEN ATOM, A LOWER ALKYL GROUP, A LOWER ALKOXY GROUP, A HALOGEN ATOM, HYDROXY GROUP, NITRO GROUP, CYANO GROUP, AN ACYL GROUP, TRIFLUOROMETHYL GROUP, AMINO GROUP, AN ACYLAMINO GROUP, A N-mono(lower alkyl)amino group, A N-di(lower alkyl)amino group, AN ACYLOXY GROUP, CARBOXYL GROUP, AN ALKOXYCARBONYL GROUP, CARBAMOYL GROUP, A N-mono(lower alkyl)carbamoyl group, A N-di(lower alkyl)carbamoyl group, A LOWER ALKYLTHIO GROUP, A LOWER ALKYLSULFINYL GROUP OR A LOWER ALKYLSULFONYL GROUP; R4 represents HYDROGEN ATOM, A LOWER ALKYL GROUP, A CYCLOALKYL GROUP, AN ARALKYL GROUP, AN ARYL GROUP OR PHENACYL GROUP; R5 represents HYDROGEN ATOM OR A LOWER ALKYL GROUP; A represents AN ALKYLENE GROUP WHICH MAY BE STRAIGHT OR BRANCHED; AND Y represents OXYGEN ATOM OR SULFUR ATOM WHICH COMPRISES REACTING A COMPOUND HAVING THE FORMULA WHEREIN R1, R2, R3, R4, Y and A are as defined above or a   A process for the preparation of a benzodiazepine compound having the formula

United States Patent [191 Tachikawa et al.

PROCESS FOR THE PREPARATION OF BENZODIAZEPINE COMPOUNDS Inventors: RyujiTachikawa; l-liromu Takagi;

Tetsuo Miyadera; Toshiharu Kamioka; Mltsunobu Fukunnga; Yoichi Kawano,all of Tokyo, Japan Assignee: Sankyo Company Limited Filed: Oct. 22,1969 Appl. No.: 13,919

Foreign Application Priority Data Oct. 24, 1968 Japan 43/77500 Oct. 24,1968 Japan..... 43/77504 Apr. I7, 1969 Japan 44129968 US. Cl. 260/239.3T, 260/243 R, 260/244 R, 260/2564 F, 260/307 R, 260/306.7, 260/566 R,260/562 N, 260/295 Q, 260/287 R, 424/270, 424/272, 424/246,

Int. Cl. C07d 87/54, C07d 91/42, C07d 85/48,.

C07d 93/01, C07d 93/08, C07d 51/46, C07d 53/06, C07d 27/30 Field ofSearch 260/239.3 T, 243 R 260/244 R, 256.4 F, 307 R, 306.7

Primary Examiner-l-lenry R. Jiles Assistant ExaminerRobert T. BondAttorney-Toren and McGeady ABSTRACT A process. for the preparation of abenzodiazepine compound having the formula hydrogen atom,

a lower alkyl group, a lower alkoxy group, a halogen atom, hydroxygroup,

nitro group,

[ Aug. 28, 1973 cyano group, an acyl group, trifluoromethyl group, aminogroup, an acylamino group, a N-mono(lower alkyl)amino group, a N-di(lower alkyl)amino group, an acyloxy group, carboxyl group, analkoxycarbonyl group, carbamoyl group, a N-mono(lower alkyl)carbamoylgroup, a N-di(lower alkyl)carbamoyl group, a lower alkylthio group, alower alkylsulfinyl group or a lower alkylsulfonyl group; R representshydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkylgroup, an aryl group or phenacyl group; R, represents hydrogen atom or alower alkyl group; A represents an alkylene group which may be straightor branched; and Y represents oxygen atom or sulfur atom which comprisesreacting a compound having the formula I wherein R,, R R R.,, Y and Aare as defined above or a mixture of these compounds with a reactivederivative of a compound having the formula wherein Q represents an acidradical of a reactive ester and R is as defined above.

The benzodiazepine compounds are useful as a minor tranquilizer.

4 Claims, No Drawings PROCESS FOR THE PREPARATION OF BENZODIAZEPINECOMPOUNDS RELATED APPLICATION This application is related to applicationSer. No. 775,914, filed Nov. 14, 1968 of Ryuji Tachikawa et al.,entitled Benzodiazepine Derivatives and Process for Preparing the Same."

This invention relates to a novel process for the preparation of novelbenzodiazepine compounds. More particularly, it relates to a novelprocess for preparing a novel benzodiazepine compound having-the formulaI wherein 7' R,, R and R may be the same or different and eachrepresents hydrogen atom, a lower alkyl group, a lower alkoxy group, ahalogen atom, hydroxy group, nitro group, cyano group, an acyl group,trifluoromethyl group, amino group, an acylamino group, a N-mono(loweralkyl)amino group, a N-di(lower alkyl)amino group, an acyloxy group,carboxyl group, an alkoxycarbonyl group, carbamoyl group, a N-mono(loweralkyl)carbamoyl group, a N-di(lower alkyl)carbamoyl group, a loweralkylthiogroup, a lower alkylsulfinyl group or a lower alkylsulfonylgroup; R represents hydrogen atom, a lower alkyl group, a cycloalkylgroup, an aralkyl group, an aryl group or phenacyl group. R representshydrogen atom or a lower alkyl group; A represents an alkylene groupwhich may be straight or branched; and Y represents oxygen atom orsulfur atom. In the above formula (I), R,, R and R may occupy anyposition of the benzene ring and n shows the position number of carbonatom in the alkylene radical A; for example, n means 4 and 5' forethylene.

v In the above formula (I), the lower alkyl group can be straight orbranched alkyl group, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, sec.-butyl, tertbutyl and the like. The lower alkoxy group canbe, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and thelike. The halogen atom can be fluorine, chlorine, bromine or iodine. Theacyl group can be aliphatic and aromatic acyl group such as formyl,acetyl, propionyl, butyryl, benzoyl, toluoyl, napththoyl and the like.The acylamino group can be, for example, acetylamino, propionylamino,butyrylamino, benzoylamino, toluoylamino, naphthoylamino and the like.The N-mono(lower alkyl)-amino group can be, for example N-methyl,-ethyl, -propyl or -butylamino group. The N-di(lower a1kyl)amino groupcan be, for example, N-dimethyl, -diethyl, -dipropyl or dibutylaminogroup. The acyloxy group can be, for example, acetoxy, propionyloxy,butyryloxy, benzoyloxy and the like. The alkoxycarbonyl group can be,for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl and the like. The N-mono(lower alkyl)carbamoyl group canbe, for example, N-methyl, -ethyl, -propyl or -butylcarbamoyl. TheN-di(lower alkyl)carbamoyl group can be, for example, N-dimethyl,-diethyl, -dipropyl or-dibutylcarbamoyl. The lower alkylthio group canbe, for example, methylthio, ethylthio, propylthio, butylthio and thelike. The lower alkylsulfinyl group can be, for example, methylsulfinyl,ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like. The loweralkylsulfonyl group can be, for example, methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl and the like. The cycloalkyl group can be,for example, cyclopropyl, cyclopentyl, cyclohexyl and the like. Thearalkyl group can be, for example, benzyl, phenethyl and the like. Thearyl group can be, for example, phenyl, naphthyl and the like. Thealkylene group can be, for example, ethylene, propylene, trimethylene,1,2- butylene, 1,3-butylene, 2,3-butylene, tetramethylene and the like.

The benzodiazepine compounds of the above formula (I) are all novelcompounds unknown in the prior art. They have high psychosedativeactivity. More particularly, they exert both tranquilizing andantidepressant activities on the central nervous system and producecalmness and relaxation. In addition to such favourable psycholepticproperties, the benzodiazepine compounds of this invention have anextremely low toxicity to man and less tendency to produce side effects.

Thus, the benzodiazepine compounds of this invention are useful as aminor tranquilizer in the relief of various psychoneurotic depressions.

These active compounds may be employed for the treatment ofpsychoneurotic disorders in the form of a pharmaceutical preparationwhich comprises the benzodiazepine compound (I) and a pharmaceuticallyacceptable carrier.

The pharmaceutical preparation may be in the form of oral preparationsincluding tablets, capsules, powders, oral suspensions and syrups, orparenteral preparations including injectable solutions and suspensions.In making up these preparations, there may be employed any ofpharrnaceutically acceptable carriers commonly used in the art. Exampleof such carriers are pharmaceutical vehicle, binder or filler such aswater, starch, gelatin, lactose, talc, cellulosic material, magnesiumstearate, vegetable oils, gum and any other known material. Thesepharmaceutical preparations may, if desired, contain various kinds andtypes of auxiliary agents, such as preserving agents, stabilizingagents, emulsifying agents, buffers or salts for adjusting osmoticpressure and they may be also sterilized in a conventional manner.

The amount to be administered for the treatment of psychoneuroticdisorders, that is, the dosage of the active benzodiazepine compound (I)should be determined by skilled physicians taking consideration of theages and weight of patients, kinds and severities of disorders, possibleside effects and other factors, but there is usually employed the totaldaily dosage for adults of about to 100 mg., preferably in multipledoses such as three or more times a day, while larger total dailydosages may be effectively employed in some cases. Moreover, the activebenzodiazepine compound (I) of this invention may be continuously andsatisfactorily administered to man for a long period of time, forexample, about 2 to 3 weeks, based upon the severities of disorders.

Therefore, it is an object of this invention to provide a novel processfor preparing the benzodiazepine compounds (I) which are valuable minortranquilizing drugs. According to this invention, the benzodiazepinecompound of the above formula (I) can be prepared by a process whichcomprises reacting a compound having the formula (II) or (ll)l wherein RR R R A and Y are as defined above or a mixture of these compounds witha reactive derivative of carboxylic acid having the formula HOOC-CH-Qwherein R is as defined above and Q is an acid radical of a reactiveester. In the above formula (III), the group O, i.e. an acid radical ofa reactive ester means to include an acid radical of such esters ashydrohalogenic acid esters, sulfonic acid esters and phosphoric acidesters; representatives of such acid radicals being chlorine, bromine,iodine, p-toluenesulfonyloxy group, methansulfonyloxy group,diphenylphosphoryl group and the like. As the reactive derivatives ofcarboxylic acid having the formula (III), there may be employed an acidhalide, an acid anhydride and the like, all of which are derived fromthe carboxylic acid (III).

In carrying out the process of this invention, the reaction may bepreferably conducted in the presence of an acid binding agent and aninert organic solvent. As the inert solvent, there may be satisfactorilyemployed any organic solvent that would not adversely affect thereaction in the process of this invention.

Representative examples of these inert organic solvents include anaromatic hydrocarbon such as benzene, toluene or xylene; a cyclic ethersuch as dioxane or tetrahydrofuran; an ester of an organic acid such asethyl acetate, amyl acetate or butyl acetate; a halogenated hydrocarbonsuch as chloroform, dichloroethane or carbon tetrachloride;acetonitrile; dimethylforrnamide; dimethylsulfoxide; and the like Thereaction in the process of this invention, as is explained hereinabove,may be preferably conducted in the presence of an acid water to thereaction mixture, extraction of the mixture with benzene, toluene orether, drying the extract and subsequent removal of the extractionsolvent and, if desired, the crude product thus obtained may be purifiedby a conventional means, e.g., recrystallization or chromatographictechnique. In the reaction of the process of this invention, when analiphatic, aromatic or heterocyclic tertiary amine is employed as theacid binding agent, a quaternary ammonium salt having the formula (IV)or (IV)' represents a quaternary ammonium ion and X represents an anionand R,, R R R R,,, A and Y are as defined above is obtained asby-product. The quaternary ammonium salts having the formulae (IV) and(IV)' are tautomers. Examples of the quaternary ammonium ion which isrepresented by in the formulae (IV) and UV) include the followingaliphatic, aromatic or heterocyclic quaternary ammonium ions;

7 cm on:

In the above formula, R represents a lower alkyl group, R representshydrogen atom or a lower alkyl group and n is an integer from 0 to 3.

Examples of the anion which is represented by X include an inorganicanion such as chloride-, bromideor sulfate-ion or an organic anion suchas acetate-, picrate-, benzoateor p-toluene-sulfonatc-ion. Thequaternary ammonium salts having the formula (IV) or (IV )1 are obtainedin large quantities when the reaction is carried out at a lowertemperature and in the presence of an excess amount of an aliphatic,aromatic or heterocyclic tertiary amine. The quaternary ammonium saltshaving the formula (IV) or (IV)' are sparingly soluble in water,benzene, toluene and ether so that they can be isolated as theinsolubles in the abovementioned extraction procedure and purified byrecrystallization from a suitable organic solvent such as ethanol.

The quaternary ammonium salts are easily converted to the benzodiazepinecompounds (I) by heating in the absence or presence of a solvent. Whenthe reaction is carried out in the absence of a solvent, crystals of thequaternary ammonium salts (IV) or (IV)' are heated at a temperature inthe neighborhood of the melting decomposition point thereof. When thereaction is carried out in the presence of a solvent, there may besatisfactorily employed any of organic solvents that would not adverselyaffect the reaction and in which the starting material employed would besoluble. Preferably a high boiling solvent such as p-cymene,dimethylformamide or dimethylsulfoxide is employed.

The quaternary ammonium salts (IV) or (IV)' dissolved in anabove-mentioned solvent are heated under atmospheric pressure or underpressure nearly at a temperature of melting (decomposition) pointthereof. The heating period may be varied depending upon the kind andtype of the starting materials employed. After completion of thereaction, the desired product (I) may be easily recovered from thereaction mixture by a conventional means. For instance, when the solventis em ployed, the solvent is distilled off from the reaction mixture.The reaction mixture which is obtained by conducting the reaction in theabsence of the solvent is extracted with dichloromethane or chloroform.The extract is dried and the solvent is distilled off. The residue isrecrystallized from a suitable solvent such as ethanol, or if desired,silica gel chromatographic treatment is applied before therecrystallization.

The compounds having the formula (II) and (ll) employed as startingmaterials in the present invention are tautomers and exist as thestructure represented by the formula (II) or (11) or in equilibriumstate thereof in various proportions, depending upon the kind of thesubstituents, e.g., R R R R Y and A and the condition wherein thecompound is present, e.g., temperature or solvent. Almost all thecompounds (11) are oily substances. The oily substance is converted tothe crystalline substance of the compound (II)' by standing or treatmentwith an organic solvent. The crystalline substance thus obtained can beconverted to an oily substance substantially containing the compound(II) by vacuum distillation.

The compound having the formula (II) or (11) or the mixture thereof canbe prepared by reacting an aminobenzophenone derivative having theformula NHR whereini R51, and fame as defined above with i an aminecompound having the formula wherein Y and A are as defined above.

In carrying out said reaction, for example, the aminobenzophenonederivative (V) is admixed with an excess'of an equimolar amount of theamine compound (VI). The mixture is heated under azeotropic separationof water to remove water formed in the reaction. The reaction mixture isfurther distilled under reduced pressure to obtain an oily residuepredominantly containing the compound (II). The oily residue can beemployed as the starting material in this invention without furthertreatment as described hereinbelow. The oily substance substantiallycontaining the compound (II) can be obtained by vacuum distillation ofsaid oily residue. When the oily substance is left or crystallized froman organic solvent, the crystalline substance having the formula (II)'is obtained.

The following examples illustrate the process for preparing thecompounds (II) and (11) which are employed in the present invention asstarting materials.

Preparation of a starting material2-(5-Chloro-2-aminophenyl)-2-phenyl-5- methyloxazolidine A mixture of11.8 g of S-chloro-2- aminobenzophenonc and 12.0 g of isopropanolarninewas heated at l-l80 C for 4 hours. After cooling, the excessisopropanolamine was distilled off under reduced pressure and theresidue was distilled in vacuo to give the oily material, which wassubstantially composed of 2-(S-chloro-Z-amino-phenyl)-2-phenyl-5-methyloxazolidine, boiling at l59-l62C/5.0 X 10 mml-lg.

Analysis:

Calculated for c,,H,,0N,c|;

C, 66.54; H, 5.93; N, 9.70; CI, 12.28.

Found: C, 66.70; H, 5.93; N, 9.52; Cl, 12.56

Following the substantially same procedure as described above, thefollowing oxazolidine derivatives were similarly prepared from thecorresponding benzophenones and amines:

2-( 3 ,5 -dimethyl-2-aminophenyl )-2-phenyl-5 methyloxazolidine (b.p.l64-l70C/2.0 X 10" mmHg); 2-(5-chloro-2-aminophenyl)-2-phenyloxazolidine(b.p. l9l-l94C/8.0 X 10" mml-lg); 2-(S-bromo-Z-aminophenyl)-2-phenyl-5-methyloxazolidine (b.p. l79-l82C/8.l X10 mml-lg);

2-(5-bromo-2-aminophenyl)-2-(2-chlorophenyl)-5- methyloxazolidine (b.p.l89-l93C/8.0 X l" 8);

2-( S-chloro-Z-aminophenyl )-2-( 2-chlorophenyl)oxazolidine (b.p.193-l94C/6.0 X 10" mmHg);

2-( -chloro-2-aminophenyl)-2-( 2-chlorophenyl )-5 methyloxazolidine(b.p. l83l84C/4.4 X ms);

2-(3,5-dimethyl-2-aminophenyl)-2- phenyloxazolidine {b.p. l74-l77C/1.0 X10" s); 2-[2-Amino-5-chloro-a-(2-chlorophenyl)benzylideneamino1ethanol Amixture of 10.6 g of S-chloro-Z-amino-ochlorobenzophenone and 9.8 g ofZ-aminoethanol was heated at l70-l80C for 5 hours. After cooling, theexcess Z-aminoethanol was distilled off under reduced pressure and theresidue was recrystallized from benzene to give the desired product ascrystals melting at l2l-l23C.

Following the substantially same procedure as described above, variousbenzylideneaminoethanol derivatives included in the above formula (11)were similarly prepared from the corresponding benzophenones and amines.

The following examples are given for the purpose of illustrating of thisinvention. It is to be understood that these examples should not beconstrued as limiting the scope of this invention.

Example 1 7-Chloro-5-phenyl-[5,4-b]-5 '-methyloxazolidino-2,3,4,.5-tetrahydro-lH-l ,4-benzodiazepin -2-one To 16 g of2-(5-chloro-2-aminophenyl)-2-phenyl-5- methyloxazolidine dissolved in180 ml of dioxane, 8.0 g of pyridine was added and the resulting mixturewas cooled in an ice-water bath with stirring. To the resulting solutionwas added 12.2 g of bromoacetyl bromide drop by drop. The temperature ofthe reaction mixture was kept below 20C during the addition of thereagent. The mixture was stirred at room temperature for an additional 3hours. At the end of this time 200 ml of toluene and 200 ml of waterwere added and then the mixture was shaken. The organic layer wasseparated from aqueous layer, dried over anhydrous sodium sulfate andthen the solvent was distilled off. The residue was recrystallized fromethanol to give the desired product melting at l86.5-l88C.

Example 2 7-Chloro-5-phenyl-[5,4-b]-oxazolidino-2,3,4,5- tetrahydrol H-l ,4-benzodiazepin -2-one Following the procedure similar to thatdescribed in Example 1 ,but substituting 2-(5-chloro-2-aminophenyl)-2-phenyloxazolidine and triethylamine for2-(5-chloro-2-aminophenyl)-2-phenyl-5- methyloxazolidine and pyridine,the desired productmelting at l75- 176C was obtained.

Example 3 7,Q-Dimethyl-S-phenyl-[5,4-b]-5'-rnethyloxazolidino-2,3,4,5-tetrahydro -ll-l-l,4-benzodiazepin -2-one Following theprocedure similar to that described in Example 1, but substituting2-(3,5-dimethyl-2- arninophenyl)-2-phenyl-5-methyl-oxazolidine andbromoacetic anhydride for 2-(5-chloro-2-arninophenyl)-2-phenyl-5-methyloxazolidine and bromoacetyl bromide, thedesired product melting at 272-273C was obtained.

Example 4 7-Bromo-5-phenyl-[5,4-b1-5'-methyloxazolidino-2,3,4,5-tetrahydro- 1 PM ,4-benzodiazepin -2-one Following the proceduresimilar to that described in Example 1, but substituting 2-(5-bromo-2-aminophenyl)-2-phenyl-5-methyloxazolidine and sodium carbonate for2-(5-chloro-2-aminophenyl)-2- phenyl-5-m e thyloxazolidine and pyridine,the desired product melting at 180.5-l82C was obtained.

Example 5 7-Bromo-5-(2"-chlorophenyl)-[5,4-b]-5'-methyloxazolidino-2,3,4,5 -tetrahydrol H l ,4- benzodiazepin -2-oneFollowing the procedure similar to that described in Example I, butsubstituting 2-(S-bromo-2- aminophenyl)-2-(2-chlorophenyl)-5-methyloxazolidine for 2-(5-chloro-2-aminophenyl)-2-phenyl-S-methyl-oxazolidine, the desired product melting at l96-l98C wasobtained.

Example 6 7-Chloro-S-(2"-chlorophenyl)-[5,4-b1-oxazolidino- 2,3 ,4,5-tetrahydrol H- l ,4-benzodiazepin -2-one Following the proceduresimilar to that described in Example 1, but substituting 2-(5-chloro-2-aminophenyl)-2-( 2-chlorophenyl)-oxazolidine for 2-(5-chloro-2-aminophenyl)-2-phenyl-5- methyloxazolidine, the desiredproduct melting at 201 -204C with decomposition was obtained.

Example 7 7-Chloro-5-(2"-chlorophenyl)[5,4-b]-5'-methyloxazolidino-2,3,4,5-tetrahydro-lH-1,4- benzodiazepin-2-oneFollowing the procedure similar to that described in Example 1, butsubstituting 2-(5-chloro-2- aminophenyl)-2-(2-chlorophenyl)-5-methyloxazolidine for 2-(5-chloro-2-aminophenyl)-2-phenyl-S-methyloxazolidine, the desired product melting at l-l92C wasobtained.

Example 8 3,7,9-Trimethyl-5-phenyl-[5,4-b] oxazolidino-2,3,4,S-tetrahydro- 1 H4 ,4-benzodiazepin -2-one Following the procedure similarto that described in Example 1, but substituting 2-(3,5-dimethyl-2-aminophenyl)-2-phenyloxazolidine and abromopropionyl chloride for2-(5-chloro-2-aminophenyly2- phenyl-5-methyloxazolidine and bromoacetylbromide, the desired product melting at 2l8-22lC was obtained.

Example 9 was poured into ice-water and extracted with dichloromethane.The extract was washed with water, dried over anhydrous sodium sulfateand then the solvent was distilled off. The residue was recrystallizedfrom ethanol to give the desired product melting at 186-l88C.

Example 7,9-Dimethyl-5-phenyl-[5,4-b]-5|'-methyloxazolidino- 2,3,4,5-tetrahydrol l-i-l ,4-benzodiazepin -2-one Following the proceduresimilar to that described in Example 9, but substituting2-(2-amino-3,5-dimethyla-phenylbenzylideneamino)-l-methylethanol andbromacetyl chloride for2-(2-amino-5-chloro-aphenylbenzylideneamino)-l-methylethanol andbromoacetyl bromide, the desired product melting at 272-273C withdecomposition was obtained.

Example 1 l 7-Chloro-5-(2"-chlorophenyl)-[5,4,-b]-oxazolidino-2,3,4,5-tetrahydro-ll-l-l ,4-benzodiazepin -2-one To a solution of 5.6 gof 2-[2-amino-5-chloro-a-(2- chlorophenyl) benzylideneamino1ethanol in80 ml of dioxane was added 2.3 g of sodium carbonate. The reactionmixture was stirred and the reaction bottle was cooled in an ice-waterbath. Eight point one grams of bromacetyl bromide was then addeddropwise to the mixture. During the addition of the reagent, thetemperature of the reaction mixture was kept below C. The stirring wascontinued further at room temperature for 3 hours. After completion ofthe reaction, the reaction mixture was poured into ice-water andextracted with dichloromethane. The extract was washed with water, driedover anhydrous sodium sulfate and then the solvent was distilled off.The residue was recrystallized from ethanol to give the desired productas crystals melting at 204C with decomposition.

Example 12 7-Chloro-5-phenyl-[5,4-b]-thiazolidino-2,3,4,5-tetrahydro-lH-1,4-benzodiazepin -2-one Following the procedure similarto that described in Example 11, but substituting2-(2-amino-5-chloro-aphenylbenzylideneamino )ethyl mercaptan for 2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneamino1ethanol, the desiredproduct melting at 24l-243C with decomposition was obtained.

Example 13 7-Chloro-9-methyl-5-phenyl-[ 5,4-b]-5methyloxazolidino-2,3,4,5-tetrahydro-lH-1,4- benzodiazepin -2-oneFollowing the procedure similar to that described in Example 9, butsubstituting 2-(2-amino-3-methyl-5- chloro-a-phenylbenzylidene-amino l-methylethanol and triethylamine for2-(2-amino-5-chloro-aphenylbenzylideneamino )-l-methylethanol andpyridine, the desired product melting at 253-254C with decomposition wasobtained.

Example 1 4 7 ,8-Dichloro-5 -phenyl-[ 5 ,4-b] -5 '-methyloxazolidino- 2,3 ,4,5 -tetrahyd ro- 1 l-l-l ,4-benzodiazepin-2-one Following theprocedure similar to that described in Example 1 l, but substituting2-(2-amino-4,5-dichloroa-phenyibenzylideneamino)- l -methylethanol for2-[2- amino-5-chloro-a-(2-chlorophenyl) benzylideneamino1ethanol, thedesired product melting at 195-l97C was obtained.

10 Example 15 7-Bromol -ethyl-5-phenyl-[ 5 ,4-b]-oxazolidino-2,3,4,5-tetrahydrol H-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example ll, but substituting2-(2-ethylamino-5- bromo-a-phenylbenzylideneamino)ethanol and potassiumcarbonate for 2-[2-amino-5-chloro-a- (2-chlor0-phenyl)-benzylideneamino]ethanol and sodium carbonate, the desiredproduct melting at 136 -l38C was obtained.

Example 16 7-Chloro-5-phenyl-[5,4-b]-oxazolidino-2,3,4,5- tetrahydro-lH-l ,4-benzodiazepin-2-one Following the procedure similar to thatdescribed in Example ll, but substituting2-(2-amino-5-chloro-aphenylbenzylideneamino) ethanol for 2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneamino]ethanol, the desired productmelting at l-l76C was obtained.

Example 17 7-Chloro-3-methyl-5-phenyl-[5,4-b]-oxazolidino-2,3,4,5-tetrahydro-ll-l-1 ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 11, but substituting2-(2-amino-5-chloro-aphenylbenzylideneamino) ethanol anda-bromopropionyl chloride for2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneamino1ethanol andbromoacetyl bromide, the desired product melting at 205-207C wasobtained.

Example 18 7-Chloro-5-o-tolyl-[5,4-b]-5'-methyloxazolidino- 2,3,4,5-tetrahydrol l-ll ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 9, but substituting 2-[2-amino-5chloro-a-(otolyl)benzylideneamino1-l -methylethanol and triethylaminefor 2-( 2-amino-5-chloro-a-phenylbenzylideneamino)-l-methylethanol andpyridine, the desired product melting at 205C with decomposition wasobtained.

Example 19 7-Chloro-5 2-chlorophenyl H 5 ,4-b ]-5methyloxazolidino-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-Z-oneFollowing the procedure similar to that described in Example 11, butsubstituting 2-[2-amino-5-chloro-oz- (2-chlorophenyl )benzylideneamino1-l methylthanol and potassium carbonate for 2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneaminolethanol and sodium carbonate, thedesired product melting at 192C with decomposition was obtained.

Example 20 7-Chlorol -methyl-5 -phenyl-[ 5 ,4-b ]-oxazolidino- 2,3,4,5-tetrahydro-1H-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 1 l, but substituting2-(2-methylamino-5- chloro-a-phenylbenzylideneamino)ethanol for 2-[2-amino-5-chloro-a-( 2-chlorophenyl)benzylideneamino1ethanol, the desiredproduct melting at 181-l83 C was obtained.

Example 21 7-Bromo-5-( 2 '-chlorophenyl H 5 ,4-b ]-oxazolidino- 2,3,4,5-tetrahydrol H-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 11, but substituting2-[2-amino-5-bromox- (2-chlorophenyl) benzylideneaminokthanol andbromoacetyl chloride for 2-[2-amino-5-chloro-a-(2- chlorophenyl)benzylideneamino]ethanol and bromoacetyl bromide, the desired productmelting at 207C with decomposition was obtained.

Example 22 7-Bromo-5-(2"-chlorophenyl)-[5,4-b]-5'- methyloxazolidino-2,3,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepin-2-one Following the proceduresimilar to that described in Example 1 l, but substituting2-[2-amino-5-bromo-a- (2-chlorophenyl) benzylideneamino1-l-methylethanol for2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneamino1ethanol, thedesired product melting at 196- 197C with decomposition was obtained.

Example 23 Example 24 7-Nitro-5-phenyl-[5,4-b]-oxaz0lidino-2,3,4,5-tetrahydro-l H- 1 ,4-benzodiazepin-2-one Following the procedure similarto that described in Example 9, but substituting 2-(Z-amino-S-nitro-aphenylbenzylideneamino)ethanol and bromoacetyl chloridefor 2-( 2-amino-5-chloro-a-phenylbenzylideneamino)- l -methylethanol andbromoacetyl bromide, the desired product melting at 2l8-220C withdecomposition was obtained.

Example 25 7-Chloro-5-(4 '-nitrophenyl)-[5 ,4-b]- methyloxazolidino-2,3,4,5 -tetrahydrol H- l ,4- benzodiazepin-Z-one Following the proceduresimilar to that described in Example 11, but substituting2-[2-amino-5-chloro-a- (4-nitrophenyl) benzylideneamino 1 1-methylethanol for 2-[ 2-amino-5 -chloro-a-( 2-chlorophenyl)benzylideneaminolethanol, the desired product melting at l93- l95C wasobtained.

Example 26 7-Chloro-5-(2"-fluorophenyl)-[5,4-b]-oxazolidino- 2 ,3 ,4 ,5-tetrahydro-ll-l-1 ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 9, but substituting2-[2-amino-5-chloro-a-(2- fluorophenyl) benzylideneamino1ethanol,triethylamine and bromoacetyl chloride for 2-(2-amino-5-chloro-a-phenylbenzylideneamino l -methylethanol, pyridine andbromoacetyl bromide, the desired product melting at l8l-l83C wasobtained.

Example 27 7-Chloro- 1 -phenacyl-5-phenyl-[ 5 ,4-b ]-5methyloxazolidino-2,3 ,4,5-tetrahydro- 1 PL] ,4- benzodiazepin-Z-oneFollowing the procedure similar to that described in Example 11, butsubstituting 2-(2-phenacylamino-5- chloro-a-phenylbenzyl-ideneamino)- l-methylethanol, potassium carbonate and bromoacetyl chloride for 2-[2-amino-5-chloro a-(2-chlorophenyl)benzylideneamino1ethanol, sodiumcarbonate and bromoacetyl bromide, the desired product melting at l--l76C was obtained.

Example 28 7-Chloro-l -benzyl-5-phenyl-[ 5 ,4-b -5mefliyloxazolidino-2,3,4,5-tetrahydro-lH-1,4- benzodiazepin-Z-oneFollowing the procedure similar to that described in Example ll, butsubstituting 2-(2-benzylamino-5- chloro-a-phenylbenzylideneamino)- l-methylethanol and bromoacetyl chloride for 2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneaminolethanol and bromoacetyl bromide, thedesired product melting at l54-l56C was obtained.

Example 29 5 -Phenyl-[ 5 ,4-b ]-5 'methyloxazolidino-2 ,3 ,4 ,5tetrahydrol H-l ,4-benzodiazepin-2-one Following the procedure similarto that described in Example 9, but substituting2-(2-amino-a-phenylbenzylideneamin0)-l-methylethanol for 2-(2-amino-5-chloro-a-phenylbenzylideneamino l -methylethanol the desired productmelting at l74-l76C was obtained.

Exmple 30 7-Chloro'5 -phenyl-{ 5 ,4-b1-4 -methyloxazolidino- 2,3 ,4,5-tetrahydro-l H-l ,4-benzodiazepin-2-one Following the procedure similarto that described in Example 9, but substituting2-(2-amino-5-chloro-aphenylbenzylideneamino)-2-methylethanol for 2-(2-amino-5 -chloro-a-phenylbenzylideneamino)- l methylethanol, the desiredproduct melting at 126- l 27C was obtained.

Example 31 7-Chloro-5-phenyl-[5,4-b]-4'-methyloxazolidino- 2,3,4,5-tetrahydrol l-l-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 9, but substituting2-(2-amino-5-chloro-aphenylbenzylideneamino)-2-methylethanol andtosyloxyacetyl bromide for2-(2-amino-5-chloro'ozphenylbenzylideneamino)-l-methylethanol andbromoacetyl bromide, the desired product melting at l26-l27C wasobtained.

Example 32 7-Bromo-5-phenyl-{5,4-b]-4-methyloxazolidino- 2,3,4,S-tetrahydro- 1 l-i-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 9, but substituting2-(2-amino-5-bromo-aphenylbenzylideneamino)-2-methylethanol for 2-(2-amino-5 -chloro-a-phenylbenzylideneamino)-l methylethanol, the desiredproduct melting at l26- l- 27C was obtained.

Example 33 7-Nitro-5-phenyl-[5,4-bI-4'-methyloxazolidino- 2,3 ,4,5-tetrahydrol H-l ,4-benzodiazepin-2-one Following the procedure similarto that described in Example 9, but substituting2-(2-amino-5-nitro-aphenylbenzylideneamino)-2-methylethanol for 2-(2-amino-5-chloro-a-phenylbenzylideneamino)-lmethylethanol, the desiredproduct melting at l82- l 83C was obtained.

Example 34 7-Chloro-5-(2"-chlorophenyl)-[5,4-b]-4'-methyloxazolidino-2,3 ,4,5-tetrahydro-l FM ,4- benzodiazepin-2-oneFollowing the procedure similar to that described in Example ll, butsubstituting 2-[2-amino-5-chloro-w (2-chlorophenyl)benzylideneamino]-2-methylethanol for 2-[2-amino-5-chloro-a-(2-chlorophenyl)benzylideneamino] ethanol, the desired product melting atl72-175C was obtained.

Example 35 7-Bromo-5-(2"-chlorophenyl)-[5,4-b]-4'-methyloxazolidino-Z,3,4,5-tetrahydrol H- 1 ,4- benzodiazepin-2 oneFollowing the procedure similar to that described in Example 9, butsubstituting 2-[2-amino-5-bromo-a-( 2-chlorophenyl)benzylideneamino]-2-methylethanol for 2-(2-amino-5-chloro-a-phenylbenzylideneamino l methylethanol the desiredproduct melting at l82- l 8- 4C was obtained.

Example 36 9-Methyl-7-chloro-5-phenyl-[ 5 ,4-b]-5 methyloxazolidino-2,3,4,5-tetrahydro-l H- l ,4- benzodiazepin-2-one A mixture of 4.4 g of3-methyl-5-chloro-2- aminobenzophenone and 3.2 g. of isopropanolaminewas heated to gentle refluxing for 4 hours. After removal of the excessof isopropanolamine by distillation under reduced pressure, 200 ml oftoluene and 3.0 g of pyridine were added to the oily residuepredominantly containing 2-(3-methyl-5-chloro-2-aminophenyl)-2-phenyl-S-methyl-oxazolidine. To the resulting solution cooled inice-water was added 5.8 g of bromoacetyl bromide drop by drop withstirring. The temperature of the reaction mixture was kept below 10Cduring the addition of the reagent. The mixture was stirred at ordinarytemperature for an additional 3 hours. At the end of this time 200 ml oftoluene and 200 ml of water were added and the mixture was shaken. Theresulting upper organic layer was separated from other parts, dried overanhydrous sodium sulfate and then the solvent was distilled off. Theresidue was recrystallized from ethanol to give 2.65 g of the desiredproduct as crystals melting at 250-253C.

Exmple 37 7 ,9-Dimethyl-5 -phenyl- 5 ,4-b -5 '-methyloxazolidino- 2 ,3,4,5 -tetrahydro- 1 l-l-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting3,5-dimethyl-2- aminobenzophenone and bromoacetic anhydride for3-methyl-5-chloro-2-aminobenzophenone and bromoacetyl bromide, thedesired product melting at 27l.5-273C was obtained.

Example 38 7-Chloro-5-phenyl-[ 5 ,4-b]-oxazolidino-2,3 ,4,5-tetrahydro-l H-14,-benzodiazepin-2-one Following the procedure similarto that described in Example 36, but substituting 5-chloro-2-aminobenzophenone, Z-aminoethanol and triethylamine for3-methyl-5-chloro-2-aminobenzophenone, isopropanolamine and pyridine,the desired product melting at l-l76C was obtained.

Example 39 7-Chloro-5-phenyl-[ 5 ,4-b]-5 '-methyloxazolidino- 2,3,4,5-tetrahydrol H- l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-chloro-2aminobenzophenone for 3-methyl-5-chloro-2- aminobenzophenone, thedesired product melting at 186.5- 188C was obtained.

Example 40 7-Bromo-5 -phenyl- 5 ,4-b -oxazolidino-2 ,3 ,4 ,5tetrahydro-l H-l ,4-benzodiazepin-2-one Following the procedure similarto that described in Example 36, but substituting 5-brom0-2-aminobenzophenone and 2-aminoethanol for 3-methyl-5-chloro-2-aminobenzophenone and isopropanolamine, the desired productmelting at l89-l9lC was obtained.

Example 41 7-Bromo-5 -phenyl-[ 5 ,4-b -5 '-methyloxazolidino- 2 ,3 ,4,5-tetrahydrol H-l ,4-benzodiazepin-2-one Following the procedure similarto that described in Example 36, but substituting 5-bromo-2-aminobenzophenone and sodium carbonate for 3-methyl-S-chloro-2-aminobenzophenone and pyridine, the desired productmelting at 180.5-182C was obtained.

Example 42 7-Chloro-5 -phenyl- 5 ,4-b] -tetrahydro-2H-l ,3 oxazino-2,3,4,5-tetrahydro- 1 H-l ,4-benzodiazepin- 2-one Following the proceduresimilar to that described in Example 36, but substituting S-chloro-Z-aminobenzophenone and B-aminopropanol for 3-methyl-S-chloro-2-aminobenzophenone and isopropanolamine, the desiredproduct melting at 22l-223C was obtained.

Example 43 7-Nitro-5-phenyl-[5,4-b]-oxazolidino-2,3,4,5- tetrahydro-lH-l ,4-benzodiazepin-2-one Following the procedure similar to thatdescribed in Example 36, but substituting S-nitro-Z aminobenzophenone,2-aminoethanol and triethylamine for3-methyl-5-chloro-2-aminobenzophenone, isopropanolamine and pyridine,the desired product melting at 2l7-22lC with decomposition was obtained.

Example 44 7-Chloro-l methyl-5 2 -chlorophenyl 5 ,4-b oxazolidino-2,3,4,5 -tetrahydrol l-l-l ,4-benzodiazepin- 2-one Following the proceduresimilar to that described in Example 36, but substitutingS-chIoro-Z-methylamino- O-chlorobenzophenone and 2-aminoethanol for 3-methyl-5-chloro-2-aminobenzophenone and isopropanolamine, the desiredproduct melting at l56- 158C was obtained.

Example 45 7-Chlorol -ethyl-5-phenyl- 5 ,4-b]-5.- methyloxazolidine-2,3,4,S-tetrahydro-l l-l-l ,4- benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-chloro-2-ethylaminobenzophenone and triethylamine for 3-methyl-5-chloro-2-aminobenzophenone and pyridine, the desired productmelting at l58-l60C was obtained.

Example 46 Example 47 7 -Chloro-5-( 2 '-tolyl 5 ,4-b 1-5'-methyloxazolidino- 2,3,4,5-tetra-hydro-1H-l ,4-benzodiazepin -2-oneFollowing the procedure similar to that described in Example 36, butsubstituting 5-chloro-2-amino-omethylbenzophenone for3-methyl-5-chloro-2- aminobenzophenone, the desired product melting at203-205C with decomposition was obtained.

Example 48 7-Chloro-5-(4' -nitrophenyl)-[5 ,4-b]-5 methylxazoiidine-2,3,4,5-tetrahydro-l H- l ,4- benzodiazepin-Z-one Following the proceduresimilar to that described in Example 36, but substituting-chloro-2-amino-pnitrobenzophenone and brornoacetyl chloride for 3-metyl-5-chloro-2-amino-benzophenone and bromoacetyl bromide, the desiredproduct melting at l93-l95C was obtained.

Example 49 7-Chloro-5-( 2' "fluorophenylH 5 ,4-b]-5methyloxazolidine-2,3 ,4,5-tetrahydrol H- l ,4- benzodiazepin-Z-oneFollowing the procedure similar to that described in Example 36, butsubstituting S-chloro-Z-amino-ofluorobenzophenone for3-methyl-5-chloro-2- aminobenzophenone, the desired product melting atl- 97-l99C with decomposition was obtained.

Example 50 7-Chloro-5-( 2 -fluor0phenyl )-[5 ,4-b]-oxazolidino- 2,3,4,5tetrahydrol H- l ,4-benzodiazepin-2-one Following the proceduresimilar tothat described in Example 36, but substituting5-chloro-2-amino-ofluorobenzophenone and Z-aminoethanol for 3-methyl-5-chloro-2-aminobenzophenone and isopropanoiamine, the desired productmelting at l8l-li83C was obtained.

Example 51 7-Bromo-5-(2"-chlorophenyl)-[5,4-b]-oxazolidino- 2,3,4,5-tetrahydrol H-l ,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 36, but substituting5-bromo-2-amino-ochlorobenzophenone and 2-aminoethanol for 3-methyl-S-chloro-2-aminobenzophenone and isopropanolamine, the desiredproduct melting at 205-207C with decomposition was obtained.

Example 52 7-Bromo-5-( 2' -chlor0phenyl H 5 ,4-b -5methyloxazolidino-2,3,4,S-tetrahydrol H-1 ,4- benzodiazepine-Z-oneFollowing the procedure similar to that described in Example 36, butsubstituting S-bromo-Z-amino-m chlorobenzophenone for3-methyl-5-chloro-2- aminobenzophenone, the desired product melting at1- 96-l98C with decomposition was obtained.

Example 53 7 ,8-Dichloro-5-phenyl-[5 ,4-b -5 '-methyloxazolidino- 2,3,4,S-tetrahydro-1H-l,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 36, but substituting4,5-dichloro-2- aminobenzophenone, sodium carbonate and bromoacetylchloride for 3-methyl-5-chloro-2- aminobenzophenone, pyridine andbromoacetyl bromide, the desired product melting at l96-197.5C wasobtained.

Example 54 7-Chloro-5-(2"-chlorophenyl)-[5,4-b1-oxazolidino- 2,3,4,5-tetrahydrol H-l ,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 36, but substitutingS-chloro-Z-amino-ochlorobenzophenone and Z-aminoethanol for 3-methyl-S-chloro-2-aminobenzophenone and isopropanolamine, the desiredproduct melting at 20l-204C with decomposition was obtained.

Example 55 7-Chloro-5-(2 '-chlorophenyl)-[ 5 ,4-bl-5methyloxazolizino-2,3,4,5-tetrahydro-l l-l-l ,4- benzodiazepine-2-oneFollowing the procedure similar to that described in Example 36, butsubstituting 5-chloro-2-amino-ochlorobenzophenone for3-methyl-5-chloro-2- aminobenzophenone, the desired product melting atl- -l92C with decomposition was obtained.

Example 56 7 ,9-Dichloro-5 -phenyl-[ 5 Ab 1 -5 '-methyloxazolidino- 2,3,4,5 -tetrahydrol l-ll ,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 36, but substituting3,5-dichloro-2- aminobenzophenone and sodium carbonate for 3-methyl-S-chloro-2-aminobenzophenone and pyridine, the desired productmeltng at 226-228C was obtained.

Example 57 3 ,7 ,9-Trimethyl-5-phenyl-[ 5 ,4-b ]-oxazolidino-2,3 ,4,5-tetrahydro'l H-l ,4-benzodiazepine-2-one Following the procedure similarto that described in Example 36, but substituting 3,5-dimethyl-2-aminobenzophenone, 2aminoethanol and a-bromopropionyl chloride for3-methyl-S-chloro-2- aminobenzo-phenone, isopropanolamine and bromoa- 17cetyl bromide, the desired product melting at 218-221C was obtained.

Example 58 7-Chloro-3 -ethyl- -phenyl-[ 5 ,4,-b -oxazolidino- 2,3 ,4 ,5-tetrahydro- 1 H-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-chloro-2-aminobenzophenone, 2-aminoethanol and a-bromo-nbutyryl chloride for3-methyl-5-chloro-2- aminobenzophenone, isopropanolamine and bromoacetylbromide, the desired product melting at l83- 184C was obtained.

Example 59 7Chloro-5-phenyl-[5,4-b]-thiazolidone-2,3,4,5- tetrahydroll-l-l ,4-benzodiazepin-2-one Following the procedure similar to thatdescribed in Example 36, but substituting 5-chloro-2- aminobenzophenoneand 2-mercaptoethylamine for 3-methyl-5-chloro-2-aminobenzophenone andisopropanolamine, the desired product melting at 241-243C was obtained.

Example 60 7-Chlorol -benzyl-5-phenyl-[ 5 ,4-b 1-5 methyloxazolidine-2,3,4,5-tetrahydrol l-l-l ,4- benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-chloro-2-benzylaminobenzophenone for 3-methyl-5-chloro-2- aminobenzophenone, thedesired product melting at l- 54-l5 7C was obtained.

Example 61 7-Chlorol -(p-chlorobenzyl)-5-phenyl-[ 5 ,4-b]-5methyloxazolidino-2,3,4,5-tetrahydrol H-1 ,4- benzodiazepin-Z-oneFollowing the procedure similar to that described in Example 36, butsubstituting 5-chloro-2-(p-chlorobenzyl)aminobenzophenone andtriethylamine for 3- methyl-S-chloro-2-aminobenzophenone and pyridine,the desired product melting at l62-163.5C was obtained.

Example 62 7-Chloro-5-phenyl-[5,4-b]-4'-methyloxazolidino-2,3,4,5-tetrahydrol l-l-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-chloro-2-aminobenzophenone and Z-amino-n-propanol for 3-methyl-S-chloro-2-aminobenzophenone and isopropanolamine, the desiredproduct melting at 126- 127C was obtained.

Example 63 7-Chloro-5-phenyl-[5,4-b]-4-methyloxazolidino-2,3,4,5-tetrahydro-1H-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-chloro-2-aminobenzophenone, 2-amino-n-propanol and tosyloxyacetyl bromide for3-methyl-5-chloro-2- aminobenzophenone, isopropanolamine and bromoacetylbromide, the desired product melting at l26- 127C was obtained.

Example 64 7-Bromo-5-phenyl-[5,4-b]-4'-methyloxazolidino- 2 ,3,4,5-tetrahydrol H- l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-bromo-2-aminobenzophenone and 2-amino-n-propanol for 3-methyl-5-chloro-2-aminobenzophenone and ISO- propanolamine, the desiredproduct melting at l26-l27C was obtained.

Example 65 7-Nitro-5-phenyl-[5,4-b]-4'-methyloxazolidino- 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 36, but substituting 5-nitro-2-aminobenzophenone and Z-aminopropanol for 3-methyl-S-chloro-2-aminobenzophenone and isopropanolamine, the desiredproduct melting at l82-l83C was obtained.

Example 66 Example 67 7-Bromo-5-( 2 '-chlorophenyl 5 ,4-b -5methyloxazolidino-Z,3,4,5-tetrahydro-l l-l-l ,4- benzodiazepineQ-oneFollowing the procedure similar to that described in Example 36, butsubstituting 5-bromo-2-amino-ochlorobenzophenone and Z-amino-n-propanolfor 3- methyl-S-chloro-2-aminobenzophenone and isopropanolamine, thedesired product melting at l82-l84C was obtained.

Example 68 7-Chloro-5-phenyl-[5,4-b]-oxazolidino-2,3,4,5- tetrahydrolH-l ,4-benzodiazepine-2-one Five point three grams ofN-[4-chloro-2-(2'-phenyl- 2'-oxazolidinyl)phenyl]carbamoylmethyltriethylammonium bromide in 40 ml ofdimethylformamide was heated under reflux for 24 hours. The solvent wasdistilled off from the reaction mixture and the residue was extractedwith dichloromethane. The dichloromethane extract was washed with water,dried over anhydrous sodium sulfate and then the solvent was distilledoff. The residue was recrystallized two times from ethanol to givecrystals of the desired product melting at l74-l76C.

Example 69 7-Chloro-5 -phenyl-[ 5,4-b1-5 -methyloxazoldino- 2 ,3 ,4,5-tetrahydrol H- l ,4-benzodiazepin-2-one Three point one grams ofN-[4-chloro-2-(2-phenyl- 5'-methyl-2-oxazolidinyl) phenyl]carbamoylmethylpyridium bromide was heated at l- 200C for 1 hour. Aftercompletion of the reaction, the reaction mixture was extracted withchloroform. The chlorofrom extract was washed with water, dried overanhydrous sodium sulfate and then the solvent was distilled off. Theresidue was recrystallized from ethanol to give crystals of the desiredproduct melting at l86.5 1 88C.

Example 70 7-Nitro-5 -phenyl-[ ,4-b ]-5 -methyloxazolidine-2,3,4,5-tetrahydro-1H-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 69, but substitutingN-[4-nitro-2-(2'-phenyl- 5'-methyl-2-oxazolidinyl) phenyl]carbamoylmethyldimethylanilinium bromide for N-[4-chloro-2-(2'- phenyl-S'-methyl-2 oxazolidinyl )phenyl lcarbamoylmethylpyridinium bromide, thedesired product melting at 208-209C was obtained.

Example 71 7-Chloro-5-(2"-fluorophenyl)-[5,4-b1-oxazolidino- 2,3 ,4,S-tetrahydro-IH-1,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 68, but substitutingN-[4-chloro-2-(2'-ofluorophenyl-Z-oxazolidinyl)phenyl]carbamoylmethyl-pyridinium bromide and p-cymene for N-[4-chloro-2-(2'-phenyl-2'- oxazolidinyl)phenyllcarbamoylmethyltriethylammoniumbromide and dimethyl formamide, the desired product melting at l8l-l83Cwas obtained.

Example 72 Example 73 7-Chloro-5-(4' '-nitrophenyl)-[ 5 ,4-b]-5methyloxazolidino-Z,3,4,5-tetrahydro-l H-1 ,4- benzodiazepine-Z-oneFollowing the procedure similar to that described in Exmple 69, butsubstituting N-[4-chloro-2-(2'-pnitrophenyl-S '-methyl-2oxazolidinyl)phenyl]carbamoylmethyl-pyridinium p-toluenesulphonate forN-[4-chloro-2-(2'-phenyl-5'- methyl-2-oxazolidinyl)phenyl]carbamoylmethylprydinium bromide, the desired product melting atl93-l95C was obtained.

Example 74 7-Chloro-5-( 2 '-chlorophenyl 5 ,4-b l-oxazolidino-2,3,4,S-tetrahydrol H-l ,4-benzodiazepine-2-one Following the procduresimilar to that described in Example 69, but substitutingN-[4'chloro-2-(2 O- chlorophenyl-Z'-oxazolidinyl)phenyllcarbamoylmethyl-pyridinium bromide for N-{4-chloro-2-(2'-phenyl-5 '-m ethyl-2 '-oxazolidinyl )phenyl jcarbamoylrnethylpyridiniumbromide, the desired product melting at l-204C with decomposition wasobtained.

Example 7-Chloro-5-(2"-chlorophenyl)-[5,4-b1-5- methyloxazolidinyl-2,3,4 ,5 -tetrahydrol H-l ,4- benzodiazepine-Z-one Following the proceduresimilar to that described in Eample 69, but substitutingN-[4-chloro-2-(2'-ochlorophenyl-S '-methyl-2oxazolidinyl)phenyllcarbamoylmethyl-pyridinium bromide forN-[4-chloro-2-(2'-phenyl-5-methyl-2'-oxazolidinyl)phenylIcarbamoylmethylpyridinium bromide, the desiredproduct melting at l90-l92C was obtained.

Example 76 7-Chlorol -methyl-5 -(2 -chlorophenyl H 5 ,4-boxazolidino-2,3,4,5-tetrahydrol l-l-l ,4- benzodiazepine-Z-one Followingthe procedure similar to that described in Example 69, but substitutingN-[4-chloro-2-(2'-ochlorophenyl-Z'-oxazolidinyl)phenyl]-N-methylcarbamoylmethyl-dimethylanilinium chloride for N-[4-chloro-2-( 2 '-phenyl-5 '-methyl-2oxazolidinyl)phenyl]carbamoylmethyl-pyridinium bromide, the desiredproduct melting at l55-158C was obtained.

Example 77 7-Chloro-5-(2' '-tolyl 5 ,4-b1-5 -methyloxazolidino- 2 ,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-one Following the proceduresimilar to that described in Example 69, but substitutingN-[4-chloro-2-(2'-o-tolyl- 5'-methyl-2'-oxazolidinyl)phenylicarbarnoylmethylpyridinium bromide for N-[4-chloro-2-(2'-phenyl-5methyl-2'oxazolidinyl)phenyllcarbamoylmethylpyridinium bromide, thedesired product melting at 20- 3-205C was obtained.

Example 78 7-Chloro5-phenyl-[5,4-b]-tetrahydro-2H-l ,3-oxazino- 2 ,3,4,5-tetra-hydrol l-l-l ,4-benzodiazepin-2-one Following the proceduresimilar to that described in Example 69, but substitutingN-[4-chloro-2-(2'- phenyl-2 '-tetrahydro-2H-l ,3-oxazinyl)phenyllcarbamoylmethyl-pyridinium bromide forN-[4-chloro-2-(2'-phenyl-5'-methyl-2'-oxazolidinyl)phenyl]carbamoylrnethyl-pyridinium bromide, the desiredproduct melting at 220.5-223C was obtained.

Example 79 7 ,9-Dimethyl-5 -phenyl-[ 5 ,4-b]-5 '-methyloxazolidino- 2 ,3,4,5 -tetrahydro-1H-1,4-benzodiazepin-2-one Following the procdduresimilar to that described in Example 68, but substitutingN-[4,6-dimethyl-2-(2'- phenyl-S'-methyl-2-oxazolidinyl)phenyl1carbamoylmethyl-pyridinium chloride forN-{ 4-chloro-2-(2-phenyl-2'-oxazolidinyl)phenyllcarbamoylmethyltriethylammonium bromide,the desired product melting at 27l-273C was obtained.

Example 80 9-Methyl-7-chloro 5-phenyl-[5 ,4-b1-5 methyloxazolidino-Z ,3,4,5-tetrahydro- 1 H4 ,4- benzodiazepin-Z-one Following the proceduresimilar to that described in Example 69, but substitutingN-[4-chloro-6-methyl-2- (2.'-phenyl-5 '-methyl-2oxazolidinyl)phenyllcarbamoylmethyldimethylanilinium bromide forN-[4-chloro-2-(2'- phenyl--methyl-2'-oxazolidinyl)phenyl]carbamoylmethyl-pyridinium bromide, the desired product melting at252-253C was obtained.

Example 81 7-Chloro-5-phenyl-[5,4-b]-thiazolidino-2,3,4,5- tetrahydro- 1H-l ,4-benzodiazepin-2-one Following the procedure similar to thatdescribed in Example 69, but substitutingN-[4-chloro-2-(2'-phenyl-2'-thiazolidinyl)phenyl]carbamoylmethylpyridinium bromide for N-[4-chloro-2-(2'-phenyl-5-methyl-2-oxazolidinyl)phenyl]carbamoylmethylpyridinium bromide, thedesired product melting at 24- 1-243C was obtained.

Example 82 7-Chloro-l-ethyl-5-phenyl-[5,4-b1-5'- methyloxazolidino-2,3,4,5 -tetrahydro-ll-l-1 ,4- benzodiazepin-Z-one Following the proceduresimilar to that described in Example 69, but substitutingN-[4-chloro-2-(2'- phenyl-5 -methyl-2 '-oxazol-idinyl )phenyl] -N-ethylcarbamoylmethyl-pyridinium chloride for N-[4- chloro-2-( 2-phenyl-5 '-methyl-2 oxazolidinyl)phenyl]carbamoyl-methyl-pyridiniumbromide, the desired product melting at l58-l60C was obtaind.

Example 83 Example 84 7-Chloro-3-ethyl-5-phenyl-[5,4-bl-oxazolidino-2,3,4,5-tetrahydro- 1 11-1 ,4-benzodiazepine-2-one Following theprocedure similar to that described in Example 69, but substitutinga-ethyl-N-[4-chloro-2- (2 '-phenyl-2 -oxazolidinyl) phenyl]carbamoylmethylpyridinium bromide for N-[4-chloro-2-(2-phenyl-5'-methyl-2'-oxazolidinyl)phenyl]carbamoylmethylpyridinium bromide, thedesired product melting at 18- 3-l84C was obtained.

Example 85 7-Chloro-l-benzyl-5-phenyl-[5,4-b]-5'-methyloxazolidino-Z,3,4,5-tetrahydro-l H- l ,4- benzodiazepino-Z-oneFollowing the procedure similar to that described in Example 69, butsubstituting N-[4-chloro-2-(2- phenyl-5 -methyl-2 -oxazolidinyl)phenyl-l-N- benzylcarbamoylmethyl-pyridinium bromide for N-[4-chloro-2-(2-phenyl-5'-methyl-2'-oxazolidinyl)phenyl]carbamoylmethyl-pyridinium bromide, the desiredproduct melting at 154-l57C was obtained.

Example 86 7-Chloro-5-phenyl-[5 ,4-b]-5 '-methyloxazolidino- 2 ,3,4,5-tetrahydrol H- 1 ,4-benzodiazepine-2-one A mixture of l 1.8 g of5-chloro- 2aminobenzophenone and 12.0 g of isopropanolamine was heatedat l-l80C for 4 hours. After removal of the excess isopropanolamine bydistillation under reduced pressure, ml of dioxane and 8.0 g of pyridinewere added to the resulting oily residue predominantly containing2-(5-chloro-2-aminophenyl)-2-phenyl-5- methyloxazolidine. To theresulting solution cooled in an ice-water bath was added 12.2 g ofbromoacetyl bromide drop by drop with stirring. During the addition ofthe reagent, the temperature of the reaction mixture was kept below 20C.The mixture was stirred at room temperature for additional 3hours. Atthe end of this time 300 ml of toluene and 250 ml of water were addedand then the mixture was shaken and stood. The mix ture separated tothree layers, i.e., the upper organic layer, lower aqueous layer andprecipitated oily layer. The upper organic layer separated therefrom wasdried over anhydrous sodium sulfate and then the solvent was distilledoff. The residue was recrystallized from the ethanol to give the desiredproduct melting at l86.5-188C.

The oily layer separated from the reaction mixture was washed with asmall amount of toluene and of water, added ethanol to givemicro-crystalline substances. After filtering, washing with ethanol anddrying, there were obtained micro-crystals of N-[4-chloro-2-(2'-phenyl-5 -methyl-2 -oxazolidinyl)phenyl1carbamoylmethyl-pyridiniumbromide.

Three point one grams of said pyridinium salt was heated at 180-200C forabout 1 hour. After completion of the reaction, the reaction mixture wasextracted with chloroform. The chloroform extract was washed with water,dried over anhydrous sodium sulfate and then the solvent was distilledoff. The residue was recrystallized from ethanol to give the desiredproduct.

Example 87 7-Chloro-5-(2 '-chlorophenyl)-[ 5 ,4-b1-5methyloxazolidino-2,3 ,4,5-tetrahydrol l-l-l ,4- benzodiazepin-Z-oneFollowing the procedure similar to that described in Example 86, butsubstituting 5 chloro-2-amino-ochlorobenzophenone for 5-chloro-2-aminobenzophenone, the pyridinium salt, i.e. N-[4- chloro-2-( 2'-O-chlorophenyl-5 -methyl-2oxazolidinyl)phenyl]carbamoylmethylpyridinium bromide, and the desiredproduct melting at -l92C was obtained.

Example 88 7-Chlorol -ethyl-5-phenyl-[ 5 ,4-b -5 methyloxazolidino-2,3,4,5 -tetrahydro-l l-i-l ,4- benzodiazepin-Z-one Following the proceduresimilar to that describd in Example 86, but substituting 5chloro-2-ethylaminobenzophenone and tri-ethylarnine for5-chloro-2-aminobenzophenone and pyridine, the quaternary ammonium salt,i.e. N-[4-chloro-2-(2-phenyl- 5 '-methyl-2-oxazolidinyl)phenyl ]-N-ethylcarbamoylmethyl-triethylammonium bromide and the desired productmelting at l58-160C was obtained.

Example 89 7-Chloro-5-phenyl-[5,4-b]-oxazolidino-2,3,4,5 tetrahydrol H-l,4-benzodiazepin-2-one Following the procedure similar to that describedin Example 86, but substituting Z-aminoethanol and triethylamine forisopropanolamine and pyridine, the quaternary ammonium salt, i.e.N-[4-chloro-2-(2fphenyl-2'-oxazolidinyl)phenyl]carbamoylmethyltriethylammoniumbromide, and the desired product melting at 174 -176C was obtained.

Example 90 Y Ra wherein R R and R may be the same or different and eachrepresents:

hydrogen atom,

a lower alkyl group,

a lower alkoxy group,

a halogen atom,

nitro group,

cyano group,

an acyl group selected from the group consisting of lower alkanoyl,benzoyl, toluoyl and naphthoyl groups,

trifluoromethyl group,

amino group,

an acylamino group selected from the group consisting of loweralkanoylamino, benzoylamino, toluoylamino and naphthoylamino groups,

a N-mono(lower alkyl)amino group,

a N-di(lower alkyl)amino group,

an acyloxy group selected from the group consist ing of loweralkanoyloxy and benzoyloxy groups,

carboxyl groups,

a lower alkoxycarbonyl group,

carbamoyl group,

a N-mono(lower alkyl)carbamoyl group,

a N-di(lower alkyl)carbamoyl group,

a lower alkylthio group,

a lower alkylsulfinyl group or a lower alkylsulfonyl group;

R represents hydrogen atom,

a lower alkyl group, a lower cycloalkyl group, a phenyl or naphthylgroup, benzyl or phenethyl group, chlorbenzyl group or phenacyl group; Rrepresents hydrogen atom or a lower alkyl group; A represents analkylene group having from 2 to 4 carbon and which may be straight orbranched; and Y represents an oxygen atom or a sulfur atom whichcomprises reacting a compound having the formula (II) or (11) wherein RR R R Y and A are as defined above or a mixture of these compounds witha halogenide or anhydride of a carboxylic acid having the formula 5(III) wherein Q represents an acid radical of a hydrohalogenic acidester, a sulfonic acid ester or a phosphoric acid ester and R is asdefined above in the presence of an inert organic solvent.

2. A process for the preparation of a compound having the formula (I)hydrogen atom,

a lower alkyl group,

a lower alkoxy group,

a halogen atom,

a nitro group,

cyano group,

an acyl group selected from the group consisting of lower alkanoyl,benzoyl, toluoyl and naphtoyl groups,

trifluoromethyl group,

amino group,

an acylamino group selected from the group consisting of loweralkanoylamino, benzoyl-amino and naphthoylamino groups, a N-mono(loweralkyl)amino group, a N-di(lower alkyl)amino group, an acyloxy groupselected from the group consisting of lower alkanoyloxy and benzoyloxygroups, carboxyl groups, a lower alkoxycarbonyl group, carbamoyl group,a N-mono(lower alkyl) carbamoyl group, a N-di(lower alkyl) carbamoylgroup, a lower alkylthio group, a lower alkylsulfinyl group or a loweralkylsulfonyl group; R represents a hydrogen atom, a lower alkyl group,a lower cycloalkyl group, a phenyl or naphthyl group, benzyl orphenethyl group, chlorbenzyl group or phenacyl group; R representshydrogen atom or a lower alkyl group; A represents an alkylene grouphaving from 2 to 4 carbon atoms and which may be straight or branched;and Y represents an oxygen atom or a sulfur atom which comprisesreacting a compound having the formula (II) or (11) wherein R R R R,, Yand A are as defined above or a mixture of these compounds with ahalogenide or anhydride of a carboxylic acid having the formula R5 (III)wherein Q represents an acid radical or a hydrohalogenic acid ester, asulfonic acid ester or a phosphoric acid ester and R is as defined abovein the presence of a tertiary amine selected from the group consistingof trimethylamine, triethylamine, dimethylaniline, diethyl-aniline andpyridine to produce a mixture of compounds of the formulae (l) and (IV)or (IV)' wherein R,, R R R R;, Y and A are as defined above, the grouprepresents a quaternary ammonium ion selected from the group consting oftrimethylammonium, triethylammonium, dimethylanilinium, diethylaniliniumand pyri dinium and X represents an anion selected from the groupconsisting of chloride, bromide, sulfate, acetate, picrate, benzoate andp-toluenesulfonate, separating the compound having the formula (IV) or(IV) from the compound having the formula (I) and heating the compoundhaving the formula (IV) or (IV) thus obtained at a temperature in theneighborhood of the melting point or decomposition point of saidcompound having the formula (IV) or (lV).

3. Process for the preparation of a compound having the formula (1) R4R1 i i-o 0 I CHR5 R1 i"? Y-A wherein R R and R may be the same ordifferent and each represents hydrogen atom,

a lower alkyl group,

a lower alkoxy group,

a halogen atom,

nitro group,

cyano group,

an acyl group selected from the group consist-ing of lower alkanoyl,benzoyl, toluoyl and naphthoyl groups,

trifluoromethyl group,

amino group,

an acylamino group selected from the group consistng of loweralkanoylamino, benzoylamino toluoylamino and naphthoylamino groups,

a N-mono( lower alkyi)amino group,

a N-di(lower alkyl)amino group,

an acyloxy group selected from the group consisting of lower alkanoyloxyand benzoyloxy groups,

carboxyl group,

a lower alkoxycarbonyl group,

carbamoyl group,

a N-mono( lower alkyl)carbamoyl group,

a N-di(lower alkyl) carbamoyl group,

a lower alkythio group,

wherein T1,, R R R R,,, Y and A are as defined above, the grouprepresents a quaternary ammonium ion selected from the group consistingof trimethylammonium, triethylammonium, dimethylanilinium,diethylanilinium and pyridinium, and X- represents an anion selectedfrom the group consisting of chloride, bromide, sulfate, acetate,picrate, benzoate and p-toluenesulfonate, at a temperature in theneighborhood of the melting point or decomposition point of saidcompound having the formula (IV) or (lV)'.

4. The process of claim 1 wherein reaction is conducted in the presenceof an acid binding agent.

2. A process for the preparation of a compound having the formula (I) 3.Process for the preparation of a compound having the formula (I)
 4. Theprocess of claim 1 wherein reaction is conducted in the presence of anacid binding agent.